Innate Immune regulation of helminth-induced inflammation

蠕虫引起的炎症的先天免疫调节

• 批准号: 9078287
• 负责人: Mark Christopher Siracusa
• 金额: $ 39.75万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9078287
• 关键词: Address; Affect; Agonist; Carbonic Anhydrase Inhibitors; Cells; Cessation of life; Characteristics; Chronic; Data; Development; Dichloromethylene Diphosphonate; Disease; Enzyme Activation; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Epilepsy; Equilibrium; Event; Exhibits; FDA approved; Family; Family member; Glaucoma; Goblet Cells; Helminths; Hematopoietic; Human; Hyperplasia; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Inflammation; Intestines; Kinetics; Liposomes; Literature; Mediating; Metabolic; Molecular; Morbidity - disease rate; Mucous body substance; Mus; Parasites; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Population; Prevalence; Production; Public Health; Recruitment Activity; Regulation; Role; Stem cells; Testing; Th2 Cells; Therapeutic; Tissues; Trichinella; Trichinella spiralis; Ulcer; Wound Healing; base; carbonate dehydratase; combat; cytokine; enzyme activity; health economics; in vivo; macrophage; mast cell; monocyte; novel; prevent; public health relevance; response; stem

 DESCRIPTION (provided by applicant): Helminth infections, including Trichinella spiralis, infect approximately 2 billion people worldwide and represent a significant public health concern. To combat these parasites the mammalian immune system has evolved mechanisms to maintain a delicate balance between promoting beneficial inflammation needed to reduce parasitic burdens and limiting pathologic inflammation in order to maintain tissue integrity. The importance of maintaining this balance is evident by the severe pathology that presents in patients exhibiting dysregulated immune responses to helminthes. Despite the importance of balancing protective and pathologic responses in the context of helminth infections, the cellular and molecular events that regulate these pathways remain unknown. It is well established that type 2 responses, characteristic of helminth-induced immune responses in humans and mice, are required to both promote worm clearance and limit infection- induced tissue damage. Our recent studies have demonstrated that specialized helminth-induced hematopoietic stem/progenitor cells (HSPCs) enter peripheral tissues, develop into mast cells and promote TH2 cytokine-dependent immunity to Trichinella spiralis. In addition, our novel preliminary data reveal that helminth-induced HSPCs upregulate Carbonic anhydrase enzymes, a family of enzymes that regulate pH and are targeted therapeutically to treat epilepsy and glaucoma. Further, blocking Car enzyme activity via treatment with FDA approved pan Car inhibitors was sufficient to prevent murine and human mast cell development in vitro and mast cell responses, TH2 cytokine production and protective immunity to Trichinella in vivo. Moreover, our preliminary studies indicate that Car-dependent mast cells promote monocyte responses and the presence of intestinal alternatively activated macrophage populations. These data indicate that pharmacologic manipulation of Car enzyme activation could be employed to regulate mast cell development, TH2 cytokine- mediated inflammation and wound healing responses in the context of helminth infections. Based on our new data, two specific aims will address the following questions: (i) Can pharmacologic inhibition or activation of specific Car enzyme family members be employed to regulate Trichinella-induced mast cell responses and TH2 cytokine-mediated inflammation? (ii) Do monocytes cooperate with Car-dependent mast cells to promote intestinal wound healing responses following Trichinella infection? Collectively, these studies will interrogate novel aspects of innate immune mechanisms through which TH2 cytokine-mediated immunity and inflammation are initiated. We anticipate that defining the mechanisms through which Car enzymes regulate helminth- induced mast cell responses, Th2 cytokine production and intestinal pathology will significantly inform new immune therapeutic strategies to treat helminth infections and their associated morbidities.

 描述（由申请人提供）：包括旋毛虫在内的蠕虫感染感染了全世界约 20 亿人，是一个重大的公共卫生问题。为了对抗这些寄生虫，哺乳动物的免疫系统已经进化出一些机制，以在促进减少寄生虫负担所需的有益炎症和限制病理性炎症以维持组织完整性之间保持微妙的平衡。对蠕虫免疫反应失调的患者所表现出的严重病理状况表明了维持这种平衡的重要性。尽管在蠕虫感染的情况下平衡保护性反应和病理性反应很重要，但调节这些途径的细胞和分子事件仍然未知。众所周知，2 型反应是人类和小鼠体内蠕虫引起的免疫反应的特征，它是促进蠕虫清除和限制感染引起的组织损伤所必需的。我们最近的研究表明，专门的蠕虫诱导的造血干/祖细胞 (HSPC) 进入外周组织，发育成肥大细胞并促进对旋毛虫的 TH2 细胞因子依赖性免疫。此外，我们的新初步数据表明，蠕虫诱导的 HSPC 上调碳酸酐酶，碳酸酐酶是调节 pH 值的酶家族，可用于治疗癫痫和青光眼。此外，通过使用 FDA 批准的泛 Car 抑制剂治疗来阻断 Car 酶活性，足以防止小鼠和人类肥大细胞在体外的发育以及体内肥大细胞的反应、TH2 细胞因子的产生和对旋毛虫的保护性免疫。此外，我们的初步研究表明，Car 依赖性肥大细胞促进单核细胞反应和肠道替代性激活巨噬细胞群的存在。这些数据表明，Car酶激活的药理学操作可用于调节蠕虫感染情况下的肥大细胞发育、TH2细胞因子介导的炎症和伤口愈合反应。根据我们的新数据，两个具体目标将解决以下问题：（i）是否可以采用药理学抑制或激活特定 Car 酶家族成员来调节旋毛虫诱导的肥大细胞反应和 TH2 细胞因子介导的炎症？ (ii) 单核细胞是否与 Car 依赖性肥大细胞合作促进旋毛虫感染后肠道伤口愈合反应？总的来说，这些研究将探讨先天免疫机制的新方面，TH2细胞因子介导的免疫和炎症是通过这些机制启动的。我们预计，明确 Car 酶调节蠕虫诱导的肥大细胞反应、Th2 细胞因子产生和肠道病理学的机制将为治疗蠕虫感染及其相关疾病的新免疫治疗策略提供重要信息。